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DDX5 super-enhancer promote vasculogenic mimicry formation and metastasis in nasopharyngeal carcinoma by enhancing ADAM10 transcription

ABSTRACT: Antiangiogenetic therapies (AATs) have limited effects owing to most patients with cancer inevitably developing resistance to them. In this study, data generated using a nasopharyngeal carcinoma orthotopic mouse model in combination with clinical data suggested compensatory vasculogenic mimicry (VM) formation during AATs and the association of VM with poor prognosis of nasopharyngeal carcinoma. Additionally, data-independent acquisition mass spectrometry-based proteomics demonstrated that ADAM10 upregulation contributes to VM. Mechanistically, epigenetic and high-resolution chromatin interaction landscape analyses revealed that while ADAM10 does not interact with either the proximal or distal enhancers, DDX5, a transcription factor of ADAM10, is regulated by long-range looping enhancer-promoter interactions. Further analysis identified transcription factors bound to critical constituents of the DDX5 super-enhancer. Ingenol Mebutate, which docked excellently with DDX5, reversed ADAM10-mediated changes in gene expression, thereby effectively suppressing compensatory VM formation and metastasis and improving prognosis. Collectively, these findings provide insights into the clinical application of AATs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263286 | GEO | 2025/04/02

REPOSITORIES: GEO

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DDX5 super-enhancer promote vasculogenic mimicry formation and metastasis in nasopharyngeal carcinoma by enhancing ADAM10 transcription

Project description:Antiangiogenetic therapies (AATs) have limited effects owing to most patients with cancer inevitably developing resistance to them. In this study, data generated using a nasopharyngeal carcinoma orthotopic mouse model in combination with clinical data suggested compensatory vasculogenic mimicry (VM) formation during AATs and the association of VM with poor prognosis of nasopharyngeal carcinoma. Additionally, data-independent acquisition mass spectrometry-based proteomics demonstrated that ADAM10 upregulation contributes to VM. Mechanistically, epigenetic and high-resolution chromatin interaction landscape analyses revealed that while ADAM10 does not interact with either the proximal or distal enhancers, DDX5, a transcription factor of ADAM10, is regulated by long-range looping enhancer-promoter interactions. Further analysis identified transcription factors bound to critical constituents of the DDX5 super-enhancer. Ingenol Mebutate, which docked excellently with DDX5, reversed ADAM10-mediated changes in gene expression, thereby effectively suppressing compensatory VM formation and metastasis and improving prognosis. Collectively, these findings provide insights into the clinical application of AATs.

2025-04-02 | GSE263067 | GEO

Ingenol mebutate induces profound inflammatory and wound healing responses in uninvolved and actinic keratosis skin

Project description:We studied the transcriptomic profile of actinic keratosis (AK) skin compared to matched samples from uninvolved skin (US) before and after treatment with ingenol mebutate gel. We found that AK has a distinct mRNA profile that separates it from uninvolved skin. In particular, numerous genes associated with epidermal development and keratinocyte differentiation, such as LCE3D, SPRR1A, PI3 and several genes in the keratin family were highly expressed in AK0 skin, but not in US0, in line with the hyperkeratosis characteristic for AK. Topical application of ingenol mebutate had a profound effect on the gene expression profile, and interestingly, many more genes were affected in US than in AK. Enrichment analysis revealed that the main responses to ingenol mebutate treatment of both US and AK were inflammatory response, response to wounding, and wound healing. 30 skin biopsies were analysed; 5 from each of 6 AK patients. Before initiation of treatment, baseline biopsies were taken from one AK lesion (AK0) and from uninvolved skin (US0). A third biopsy was taken after day 1 application of ingenol mebutate from one AK lesion (AK1). The fourth and fifth biopsies were obtained one day after the second topical application with ingenol mebutate from an AK lesion (AK2) and from uninvolved skin (US2), respectively.

2016-03-31 | E-GEOD-63107 | biostudies-arrayexpress

Identification of differentially expressed genes in actinic keratosis samples treated with ingenol mebutate gel

Project description:Actinic keratosis is a common skin disease that may progress to invasive squamous cell carcinoma. Ingenol mebutate has demonstrated efficacy in field treatment of actinic keratosis. However, molecular mechanisms on ingenol mebutate response are not yet fully understood.

2020-05-18 | GSE142108 | GEO

DDX5 super-enhancer promote vasculogenic mimicry formation and metastasis in nasopharyngeal carcinoma by enhancing ADAM10 transcription

Project description:DDX5 super-enhancer promote vasculogenic mimicry formation and metastasis in nasopharyngeal carcinoma by enhancing ADAM10 transcription

| PRJNA1095534 | ENA

DDX5 super-enhancer promote vasculogenic mimicry formation and metastasis in nasopharyngeal carcinoma by enhancing ADAM10 transcription

Project description:DDX5 super-enhancer promote vasculogenic mimicry formation and metastasis in nasopharyngeal carcinoma by enhancing ADAM10 transcription

| PRJNA1096631 | ENA

Ingenol mebutate induces profound inflammatory and wound healing responses in uninvolved and actinic keratosis skin

2016-03-31 | GSE63107 | GEO

Expression data from Adam10 knock out mice and wild type

Project description:Adam10, a cell surface protease, cleaving many proteins including TNF-alpha and E-cadherin. Here we investigate the genome wide effects of Adam10 knock out on the transcriptome. Commercial microarrays (Affymetrix Mouse Gene ST 1.0) were used to generate genome wide mRNA profiles. Mouse tissue samples from n=4 wiltype skin and n=4 Adam10 knockout skin were used in the study.

2011-01-06 | E-GEOD-25480 | biostudies-arrayexpress

Proteomics analysis on COE inhibiting vasculogenic mimicry in hepatocellular carcinoma

Project description:New strategies and drugs are urgently needed to improve the treatment of hepatocellular carcinoma (HCC). Vasculogenic mimicry (VM) has been elucidated being associated with the progression of HCC and anti-VM could be a promising strategy. Celastrus orbiculatus extract (COE), a mixture of 11 terpenoids isolated from the Chinese Herb Celastrus Orbiculatus Vine, has been elucidated to be able to disrupt VM formation in HCC. This study aims to dissect and identify the potential targets of COE on anti-VM formation both in vitro and in vivo that are distinct from our previous study. Proteomics analysis was used to identify differential proteins in HCC cells treated with or without COE. Cells invasion was examined using Transwell. Matrigel was used to establish a 3-D culture condition for VM formation in vitro. RT-PCR and Western Blot were used to examine changes of mRNA and protein respectively. Clinical resected samples were applied to confirm association between VM formation and identified targets. Subcutaneous xenograft tumor model was established to observe tumor growth and VM formation in vivo. PAS-CD34 dual staining was used to detect VM in vivo. A total of 194 proteins were identified to be differentially expressed in HCC cells treated with or without COE. In the 93 down-regulated proteins EphA2 stood out to be regulated on both RNA and protein level. Disruption EphA2 using COE or NVP inhibited VM formation and decreased VM associated biomarkers. In xenograft mouse model, COE inhibited tumor growth and VM formation via down-regulating EphA2. Taken together, our results indicate that COE could be used in HCC treatment because of its promising anti-VM effect.

2021-05-03 | PXD022203 | Pride

Murine cartilage tissues (tibia): Control vs ADAM10 flox/flox-Col2a1-Cre

Project description:Transcriptional profiling of mouse cartilage tissues comparing control and mutant mice (in which the Adam10 allele was excised under the control of a Col2a1 promoter) to negate ADAM10 activity in osteochondroprogenitors. Goal was to determine the effects of the loss of ADAM10 activity on cartilage gene expression.

2019-12-11 | GSE141743 | GEO

Differential gene expression in ADAM10 over-expressing transgenic mice

Project description:In a transgenic mouse model of Alzheimer disease (AD), cleavage of the amyloid precursor protein (APP) by the α-secretase ADAM10 prevented amyloid plaque formation and alleviated cognitive deficits. Furthermore, there was a positive influence of ADAM10 over-expression on neurotransmitter-specific formation of synapses and on synaptic plasticity. To assess the influence of ADAM10 on the gene expression profile in the brain we performed microarray analysis using RNA isolated from brains of five month old mice over-expressing either the α-secretase ADAM10 or a dominant-negative mutant (dn) of this enzyme. As compared to non-transgenic wild-type mice, 355 genes were found to be differentially expressed in ADAM10 transgenic mice and 143 genes in dnADAM10 mice. A higher number of genes was found to be differentially regulated in double-transgenic mouse strains additionally expressing the human APP V717I mutant (APP[V717I]). Thus, α-secretase cleavage of over-expressed APP[V717I] alters CNS gene expression additionally. Keywords: genetic modification

2009-01-22 | GSE10908 | GEO

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